| Reference ↗
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| Title
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Protective effect of alpha-tocopherol in head and neck cancer radiation-induced mucositis: A double-blind randomized trial
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| Topic
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Vitamin E
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| Author
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Ferreira, PR, Fleck, JF, Diehl, A, Barletta, D, Braga-Filho, A, Barletta, A, Ilha, L
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| Year
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2004
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| Journal
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Head and Neck
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| DOI
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https://doi.org/10.1002/hed.10382
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Study Note
Brief summary
In this study, patients with head and neck tumors were divided into two different arms before radiotherapy. One arm received additional vitamin E throughout the radiotherapy and the other arm only a placebo. There were significantly fewer cases of oral mucositis (i.e. inflammation of the oral mucosa, a common side effect of radiotherapy) in the vitamin E group than in the other arm. In addition, less pain intensity and fewer eating restrictions were reported in the vitamin E arm. In contrast, there was no difference between the groups with regard to the average duration of mucositis, average weight loss during radiotherapy, survival time and other complications during radiotherapy. A positive aspect of this study is the adequate sample size. On the negative side, however, there was no information on the failure rate during the study and the vitamin E level was not examined to check whether the intake led to an increase in the level.
In dieser Studie wurden Patienten mit Kopf-Hals-Tumor vor der Radiotherapie in zwei verschiedenen Gruppen eingeteilt. Eine Gruppe erhielt während der gesamten Radiotherapie zusätzlich Vitamin E und die andere Gruppe nur ein Placebo. In der Vitamin E-Gruppe tauchten bedeutsam weniger Fälle von oraler Mukositis (d.h. eine Entzündung der Mundschleimhaut, eine häufige Nebenwirkung von Radiotherapie) als in der anderen Gruppe auf. Zudem wurden in der Vitamin E-Gruppe eine geringere Schmerzintensität und weniger Einschränkungen beim Essen berichtet. Kein Gruppenunterschied zeigte sich dagegen hinsichtlich der durchschnittlichen Dauer von Mukositis, dem durchschnittlichen Gewichtsverlust während der Radiotherapie, der Überlebenszeit und weiterer Komplikationen während der Radiotherapie. Positiv an dieser Studie ist die angemessene Stichprobengröße. Negativ ist jedoch, dass es keine Angaben zur Ausfallrate während der Studie gab und dass der Vitamin E Spiegel nicht untersucht wurde, um zu überprüfen, ob die Einnahme zu einem Anstieg des Spiegels geführt hat.
Study Design
| Prospective / Retrospective Prospective: forward-looking, examples include clinical trials, cohort studies, and long-term observational studies;</br>Retrospective: backward-looking, relying on existing data, examples include case-control studies and retrospective cohort studies
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Prospective
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| Monocentric / Multicentric Monocentric: conducted in one center/ hospital; </br>Multicentric: conducted in multiple centers/ hospitals
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Monocentric
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| Blinding No: Open, all parties are aware of group assignments;</br>Single: one party is unaware of group assignments (generally participants);</br>Double: two parties are unaware of group assignments (generally the participants and the researchers); </br>Triple: concealing group assignment from additional parties
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Double
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| Is randomized
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Yes
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| Cross-over Participants alternate between different treatment groups or conditions over a specified period, allowing each participant to serve as their own control
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No
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| Number of arms
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2
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Study characteristics
| Inclusion criteria
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Patients with a confirmed histologic diagnosis of cancer of the oral cavity and oropharynx referred to Radiotherapy; Admission requirements consisted of: (1) a minimal irradiated buccal mucosal area 12.2 cm2 or greater; the limits of this area, measured on verification films, were the hard palate (superior), the floor of the mouth (inferior), the anterior border of the vertical portion of the mandible (posterior), and the distal border of the irradiation field (anterior); (2) age at least 21 years; (3) Zubrod performance status grade 2 or lower; (4) tolerance of solid food at study entry
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| Exclusion criteria
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(5) no trismus, concomitant use of oral anticoagulants, previous or current history of other cancers, previous history of RT in the head and neck area, or previous or concomitant chemotherapy
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| N randomized
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54
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| Analysis PP: Per Protocol analysis, i.e. only participants included who adhered to the study protocol.</br>ITT: Intention-to-treat analysis, i.e. all randomized participants included regardless of any drop-outs or changes in assignment.</br>mITT: modified Intention-to-treat analysis can refer to analyses in which participants with missing outcome data are excluded or it can refer to analyses in which only participants who received at least one treatment dose are included. In this case, participants dropped out of the study prematurely for reasons unrelated to the treatment.
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ITT Analysis
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| Specifications on analyses
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NA
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| Countries of data collection
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Brazil
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| LoE Level of evidence
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1b Oxford 2009
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| Outcome timeline Data collection times
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Baseline + 7 weeks of radiotherapy
Median follow-Up in months: 12 (range: 2–24)
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Characteristics of participants
| Setting Refers to cancer therapy setting.</br>- Curative therapy: aims to completely eradicate a disease and achieve a full recovery; </br>- Neo-adjuvant therapy: form of curative therapy, given before the primary treatment for cancer (usually surgery); </br>- Adjuvant therapy: form of curative therapy, given after the primary treatment for cancer (usually surgery); </br>- Palliative therapy: focuses on providing relief from symptoms and improving the quality of life for patients, without necessarily targeting the underlying disease; </br>- Active surveillance: involves close monitoring of disease progression without any intervention (typically used for prostate cancer);</br>- No therapy setting: Patients who completed therapy/are currently not in cancer treatment, cancer survivors.
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Neo-adjuvant, NI
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| Types of cancer "Other Cancers" means that only a subpopulation was specified, but further unspecified cancer types were included
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Head and Neck Cancers - Oral Cancer, Head and Neck Cancers - Oropharyngeal Cancer
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| Cancer stages Early Stage: generally refers to cancer that is localized to the area where it started, mostly stages I and II;</br>Advanced Stage: cancer that has spread beyond its original site, mostly stages III and IV, with stage IV indicating distant metastasis
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Advanced Stage
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| Specifications on cancer stages
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III and IV
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| Comorbidities
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NI
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| Current cancer therapies
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Radiation therapy
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| Specifications on cancer therapies
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"Radiotherapy was provided by a Cobalt 60 unit (Theratron Phoenix) operating at 80-cm target-skin distance. Two parallel opposed fields were designed with customized alloy shielding blocks to include the tumor within a 2-cm safe margin and the upper cervical lymph nodes bilaterally. Anterior supraclavicular fields were added whether metastatic cervical lymph nodes were present or the primary tumor was located in the tonsils or tongue. A daily dose of 2 Gy/section 5 days a week was calculated at the midline up to a cumulative dose of 44 Gy/4.5 weeks. A first field reduction was made for the spinal cord, sparing up to the dose of 60 Gy/6 weeks. A second reduction was made to encompass only the tumor within 1-cm margins up to the final dose of 70 Gy/7 weeks. Patients previously treated with complete or incomplete resections were planned to receive total doses of 50 or 60 Gy in 5 and 6 weeks, respectively, with a similar technique."
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| Previous cancer therapies
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Surgery, No therapy
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| Gender
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Mixed
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| Gender specifications
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11.1% female
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| Age groups
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Adults (18+)
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| Age groups specification
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Mean (SD) = 55.4 (12.5) years
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Arms
| Arm type Active control: group receives active treatment; </br>Passive control: for example treatment as usual, waiting control, no treatment
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Intervention
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| Number of participants (arm) N randomized
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28
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| Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date
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3
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| Drop-out reasons
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Did not receive the prescribed doses: n=2 because of intense mucositis and n=1 because of death caused by tumor progression
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| Intervention
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Vitamin E
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| Dosage and regime
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Oral 400mg twice daily (immediately before radiotherapy and 8-12 hours after)
Start: Day 0 radiotherapy
Duration: entire radiotherapy
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| One-time application
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No
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| Duration in days For long-term interventions, the number of days is an estimation.</br>A value of -999 indicates that the exact duration cannot be extracted from the study due to ambiguous or incomplete information. See Outcome timeline or Dosage and regime for further information.
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49
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| Side effects / Interactions
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NI
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| Arm type Active control: group receives active treatment; </br>Passive control: for example treatment as usual, waiting control, no treatment
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Placebo
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| Number of participants (arm) N randomized
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26
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| Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date
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0
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| Drop-out reasons
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NA
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| Intervention
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Placebo
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| Dosage and regime
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Oral 500mg twice daily (immediately before radiotherapy and 8-12 hours after)
Start: Day 0 radiotherapy
Duration: entire radiotherapy
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| One-time application
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No
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| Duration in days For long-term interventions, the number of days is an estimation.</br>A value of -999 indicates that the exact duration cannot be extracted from the study due to ambiguous or incomplete information. See Outcome timeline or Dosage and regime for further information.
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49
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| Side effects / Interactions
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NI
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Outcomes
Mucositis
| Outcome type As specificed by the authors
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Primary
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| Outcome specification
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Oral mucositis
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| Type of measurement
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RTOG Acute Radiation Morbidity Scoring Criteria (Radiation Therapy Oncology Group), WHO-Scale (World Health Organisation)
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| Results during intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".
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Assesment weekly:
Number of mucositis events: vitamin E arm significantly fewer than placebo arm (36 (21.6%) vs. 54 (33.5%); RR = 0.643; 95% KI: 0.42,0.98; p = 0.038, sign.
Number of patients with pain/difficulty eating grade 2-3: vitamin E 3 (10.7%) vs. placebo arm 14 (53.8%); p = 0.0001, sign.
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| Results after intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".
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NA
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| Risk of Bias Assessment: Cochrane RoB tool 2.0
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| Bias arising from the randomization process
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?
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| Bias due to deviation from intended intervention (assignment to intervention)
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?
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| Bias due to deviation from intended intervention (adhering to intervention)
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NA
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| Bias due to missing outcome data
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?
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| Bias in measurement of the outcome
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?
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| Bias in selection of the reported result
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?
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| Other sources of bias
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?
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| Overall RoB judgment
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?
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Mucositis
| Outcome type As specificed by the authors
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Secondary
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| Outcome specification
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Length of oral mucositis
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| Type of measurement
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Observation
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| Results during intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".
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Median in weeks:
vitamin E: 1 (Range: 0-5) vs. placebo arm: 2 (range: 0-5); p = 0.102, sign.
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| Results after intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".
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NA
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| Risk of Bias Assessment: Cochrane RoB tool 2.0
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| Bias arising from the randomization process
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?
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| Bias due to deviation from intended intervention (assignment to intervention)
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?
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| Bias due to deviation from intended intervention (adhering to intervention)
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NA
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| Bias due to missing outcome data
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?
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| Bias in measurement of the outcome
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?
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| Bias in selection of the reported result
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?
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| Other sources of bias
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?
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| Overall RoB judgment
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?
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Weight
| Outcome type As specificed by the authors
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Secondary
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| Outcome specification
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Weight loss
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| Type of measurement
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Scale
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| Results during intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".
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Difference in kg (Mean baseline - mean during radiotherapy):
vitamin E arm: 4.9, placebo arm: 5.5; p = 0.249, ns.
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| Results after intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".
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NA
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| Risk of Bias Assessment: Cochrane RoB tool 2.0
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| Bias arising from the randomization process
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?
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| Bias due to deviation from intended intervention (assignment to intervention)
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?
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| Bias due to deviation from intended intervention (adhering to intervention)
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NA
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| Bias due to missing outcome data
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?
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| Bias in measurement of the outcome
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?
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| Bias in selection of the reported result
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?
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| Other sources of bias
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?
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| Overall RoB judgment
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?
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OS (Overall Survival)
| Outcome type As specificed by the authors
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Secondary
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| Outcome specification
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During the first 2 years
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| Type of measurement
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Observation
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| Results during intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".
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NA
|
| Results after intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".
|
Vitamin E arm: 32.2%, placebo arm: 62.9%
Median in months: vitamin E arm: 8.5 (Range: 2–24); placebo arm: 12.5 (range: 2–23); p = 0.126, not sign.
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| Risk of Bias Assessment: Cochrane RoB tool 2.0
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| Bias arising from the randomization process
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?
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| Bias due to deviation from intended intervention (assignment to intervention)
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?
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| Bias due to deviation from intended intervention (adhering to intervention)
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NA
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| Bias due to missing outcome data
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?
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| Bias in measurement of the outcome
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?
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| Bias in selection of the reported result
|
?
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| Other sources of bias
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?
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| Overall RoB judgment
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?
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Toxicity
| Outcome type As specificed by the authors
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Secondary
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| Outcome specification
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NA
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| Type of measurement
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NI
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| Results during intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".
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Number (%) with acute complications
Vitamin E vs. placebo arm overall: p = 0.216, not sign.
None: vitamin E: 10 (35.7), placebo arm: 9 (34.6)
mild nausea: vitamin E: 12 (42.8), placebo arm: 10 (38.5)
vomiting: vitamin E: 4 (14.3), placebo arm: 5 (19.2)
fever: vitamin E: 4 (14.3), placebo arm: 1 (3.8)
candidiasis: vitamin E: 2 (7.1), placebo arm: 4 (15.4)
bleeding: vitamin E: 2 (7.1), placebo arm: 9 (34.6)
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| Results after intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".
|
NA
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| Risk of Bias Assessment: Cochrane RoB tool 2.0
|
| Bias arising from the randomization process
|
?
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| Bias due to deviation from intended intervention (assignment to intervention)
|
?
|
| Bias due to deviation from intended intervention (adhering to intervention)
|
NA
|
| Bias due to missing outcome data
|
?
|
| Bias in measurement of the outcome
|
?
|
| Bias in selection of the reported result
|
?
|
| Other sources of bias
|
?
|
| Overall RoB judgment
|
?
|
Funding and Conflicts of Interest
| Funding
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NI
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| Conflicts of Interest
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NI
|
Further points for assessing the study
Sample
| Power analysis performed
|
?
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| - Sample size corresponds to power analysis
|
|
| - Reasons for insufficient sample size based on power analysis
|
|
| If no power analysis performed: at least moderate sample size (n >= 30 per arm)
|
?
|
| Ethnicity mentioned
|
?
|
Alternative Explanation
| Other explanations for an effect besides the investigated intervention
|
|
| - Possibility of attention effects
|
?
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| - Possibility of placebo effects
|
?
|
| - Other reasons
|
?
|
Statistics
| Correct use of parametric and non-parametric tests Testing for normal distribution only necessary if parametric tests are used, NI: use of parametric tests without report of normal distribution testing
|
|
| Correction for multiple testing
|
?
|
| Measurement of compliance
|
?
|
| Consistent reporting in numbers (figures, flowchart, abstract, results)
|
?
|
| Comprehensive and coherent reporting
|
?
|
| Cross-over
|
|
| - Sufficient washout period
|
?
|
| - Tested for carry-over effects
|
?
|
| - Tested for sequence effects
|
?
|
Interpretation of results
| Effect sizes reported (clinical vs. statistical significance)
|
?
|
| Side effects systematically recorded
|
?
|
| Side effects considered in result interpretation
|
?
|
| Ethics votum
|
?
|
Additional Notes
PRO: Ethical approval, Double-blinded, Adequate sample size according to power analysis, Intention-to-treat, High compliance (Intervention: 91.2%, Placebo: 100%)
CONTRA: Placebos also contained 2.5% Vitamin E (13 IU per 500mg), No information on dropout, Poor reporting quality (e.g., no detailed information on compliance, no information on Vitamin E levels)
